Clara cell secretory protein (CCSP) is a 16-kDa homodimeric polypeptide secreted by respiratory epithelial cells in the conducting airways of the lung. To assess the role of CCSP in bacterial inflammation and to discern whether CCSP expression is influenced by bacterial infection, CCSP-deficient [(-/-)] gene-targeted mice and wild-type mice were given Pseudomonas aeruginosa intratracheally. Infiltration by polymorphonuclear cells was significantly increased in the lungs of CCSP(-/-) mice 6 and 24 h, after the administrator of the bacteria. The number of viable bacteria isolated from the lungs in CCSP(-/-) mice was decreased compared with that in wild-type mice. Concentrations of the proinflammatory cytokines interleukin-1β and tumor necrosis factor-α were modestly increased after 6 and 24 h, respectively, in CCSP(-/-) mice. The concentration of CCSP protein in lung homogenates decreased for 1-5 days after infection and recovered by 14 days after infection. Likewise, CCSP mRNA and immunostaining for CCSP markedly decreased in respiratory epithelial cells after infection. CCSP deficiency was associated with enhanced pulmonary inflammation and improved killing of bacteria after acute pulmonary infection with P. aeruginosa. The finding that Pseudomonas infection inhibited CCSP expression provides further support for the concept that CCSP plays a role in the modulation of pulmonary inflammation during infection and recovery.